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Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic.Cross-sectional survey using four validated instruments.Sixty-two sites in Canada and the United States.Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs.None.We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures.Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness.

Background Although specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pa o 2 to F io 2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed. Results A total of 2,466 patients were enrolled. Median baseline Pa o 2 to F io 2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Trial Registry ClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Severe acute respiratory syndrome coronavirus 2 infection leads to dysregulation of immune pathways. Therapies focusing on suppressing cytokine activity have some success. Current evidence supports the use of dexamethasone in hospitalized patients requiring oxygen to decrease mortality. Interleukin-6 inhibitors, like tocilizumab and sarilumab, are also beneficial in hypoxemic patients, if used early. Janus kinase inhibition in combination with glucocorticoids is emerging as a potential therapeutic option for patients with moderate to severe symptoms. Data on the role of anakinra, hyperimmune immunoglobulin/convalescent plasma, or plasma purification are limited.

Rationale: How to provide advanced respiratory support for coronavirus disease (COVID-19) to maximize population-level survival while optimizing mechanical ventilator access is unknown. Objectives: To evaluate the use of high-flow nasal cannula for COVID-19 on population-level mortality and ventilator availability. Methods: We constructed dynamical (deterministic) simulation models of high-flow nasal cannula and mechanical ventilation use for COVID-19 in the United States. Model parameters were estimated through consensus based on published literature, local data, and experience. We had the following two outcomes: 1) cumulative number of deaths and 2) days without any available ventilators. We assessed the impact of various policies for the use of high-flow nasal cannula (with or without “early intubation”) versus a scenario in which high-flow nasal cannula was unavailable. Results: The policy associated with the fewest deaths and the least time without available ventilators combined the use of high-flow nasal cannula for patients not urgently needing ventilators with the use of early mechanical ventilation for these patients when at least 10% of ventilator supply was not in use. At the national level, this strategy resulted in 10,000–40,000 fewer deaths than if high-flow nasal cannula were not available. In addition, with moderate national ventilator capacity (30,000–45,000 ventilators), this strategy led to up to 25 (11.8%) fewer days without available ventilators. For a 250-bed hospital with 100 mechanical ventilators, the availability of 13, 20, or 33 high-flow nasal cannulas prevented 81, 102, and 130 deaths, respectively. Conclusions: The use of high-flow nasal cannula coupled with early mechanical ventilation when supply is sufficient results in fewer deaths and greater ventilator availability.

Background Investigations into the use of low tidal volume ventilation (LTVV) have been performed for patients in emergency departments (EDs) or intensive care units (ICUs). Practice differences between the ICU and non-ICU care areas have not been described. We hypothesized that the initial implementation of LTVV would be better inside ICUs than outside. Methods: This is a retrospective observational study of patients initiated on invasive mechanical ventilation (IMV) between January 1, 2016, and July 17, 2019. Initial recorded tidal volumes after intubation were used to compare the use of LTVV between care areas. Low tidal volume was considered 6.5 cc/kg of ideal body weight (IBW) or less. The primary outcome was the initiation of low tidal volume. Sensitivity analyses used a tidal volume of 8 cc/kg of IBW or less, and direct comparisons were performed between the ICU, ED, and wards. Results: There were 6392 initiations of IMV: 2217 (34.7%) in the ICU and 4175 (65.3%) outside. LTVV was more likely to be initiated in the ICU than outside (46.5% vs 34.2%; adjusted odds ratio [aOR] 0.62, 95% confidence interval [CI] 0.56-0.71, P

The efficacy of glucocorticoids in COVID-19 is unclear. This study was designed to determine whether systemic glucocorticoid treatment in COVID-19 patients is associated with reduced mortality or mechanical ventilation. This observational study included 1,806 hospitalized COVID-19 patients; 140 were treated with glucocorticoids within 48 hours of admission. Early use of glucocorticoids was not associated with mortality or mechanical ventilation. However, glucocorticoid treatment of patients with initial C-reactive protein (CRP) ≥20 mg/dL was associated with significantly reduced risk of mortality or mechanical ventilation (odds ratio, 0.23; 95% CI, 0.08- 0.70), while glucocorticoid treatment of patients with CRP

Objectives The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern. Design Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents. Setting Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1). Patients Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset. Interventions None. Measurements and main results Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality. Conclusions Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Background While specific interventions have previously demonstrated benefit in patients with the Acute Respiratory Distress Syndrome (ARDS), use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown. Research Question What is the impact of treatment variability on mortality in patients with moderate-to-severe ARDS in the United States (US)? Study Design and Methods We conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and PaO2/FiO2< 150 on positive end expiratory pressure (PEEP) > 5 cm H2O, who were admitted to 29 US centers between October 1, 2016 and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality were also assessed. Results A total of 2,466 patients were enrolled. Median baseline PaO2/FiO2 was 105 (IQR 78.0, 129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (tidal volume < 6.5 ml/kg predicted body weight, plateau pressure and/or peak inspiratory pressure < 30mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), types of modalities used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early lung protective ventilation (LPV) was correlated with SMR. Interpretation Substantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03021824

Background For patients with novel coronavirus 2019 (COVID-19) who undergo emergency endotracheal intubation, there is limited data regarding the practice, outcomes and complications of this procedure. Research Question For COVID-19 patients requiring emergency endotracheal intubation, how do the procedural techniques, the incidence of first pass success and the complications associated with the procedure compare with intubations on critically ill patients prior to the COVID-19 pandemic? Study Design and Methods We conducted a retrospective study of adult COVID-19 patients at Montefiore Medical Center who underwent first-time endotracheal intubation by critical care physicians between July 19, 2019 and May 1, 2020. The first COVID-19 patient was admitted to our institution on March 11, 2020, before which patients were designated as the pre-pandemic cohort. Descriptive statistics was used to compare groups. A Fischer’s exact test was used to compare categorical variables. A two-tailed Student’s t-test for parametric variables or a Wilcoxon rank sum test for nonparametric variables were utilized for continuous variables. Results 1,260 intubations met inclusion criteria (782 pre-pandemic, 478 pandemic). Patients during the pandemic were more likely to be intubated for hypoxemic respiratory failure (72.6% vs 28.1%; P

Background: Equitable protocols to triage scarce life-saving resources must be specified prior to disasters in order to promote transparency, trust and consistency. The degree to which proposed utilitarian protocols may maximize lives saved is unknown. Methods: We constructed a simulation model based on New York State 2015 guidelines for ventilator triage (NYS) compared to a first-come-first-served (FCFS) method for ventilator allocation under various hypothetical ventilator shortages. We included patients with laboratory confirmed SARs-CoV-2 infection admitted with respiratory failure requiring mechanical ventilation to three acute care hospitals in New York from 3/01/2020 and 5/27/2020. We estimated (1) survival rates, (2) number of excess deaths, (3) number of patients extubated early due to capacity constraints, (4) survival rates among patients not allocated a ventilator at triage or extubated early due to capacity constraints. Findings: 807 patients were included in the study. Survival rates were similar between the NYS and FCFS policies at all the survival probabilities estimated for those triaged to removal of the ventilator. At the lowest ventilator capacity, the NYS policy has an estimated survival of 28.5% (CI: 28.4-28.6), compared to 28.1% (CI: 27.7-28.5) for the FCFS policy. The two policies had similar estimated excess deaths above historical observed deaths. Interpretation: This simulation of a SOFA-based triage protocol for distributing ventilators during the COVID-19 pandemic revealed limitations in achieving the utilitarian goals these protocols are designed to fulfill. Quantifying these outcomes can inform a better balance competing moral aims. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Albert Einstein College of Medicine/Montefiore Medical Center IRB (IRB # 2020-12128) and the Columbia University IRB (IRB # AAAT4062).

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

In the setting of COVID-19 (coronavirus disease 2019)-associated moderate and severe acute respiratory distress, persistently hypoxemic patients often require prone positioning for >16 hours. We report facial pressure wounds and ear necrosis as a consequence of prone positioning in patients undergoing ventilation in the intensive care unit in a tertiary medical center in New York City.

Objectives To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality. Design Multicenter prospective cohort study between September 2017 and February 2018. Settings Thirty-four hospitals in the United States and Jordan. Patients Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor. Interventions None. Measurement and main results Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18). Conclusions The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Adjunctive strategies are an important part of the management of ARDS. However, their application in clinical practice remains inconsistent.We wished to determine the frequency and patterns of use of adjunctive strategies in patients with moderate to severe ARDS (PaoThe LUNG SAFE study was an international, multicenter, prospective cohort study of patients with severe respiratory failure, conducted in 2014 in 459 ICUs from 50 countries. The primary objective of this substudy was to determine the frequency of use of widely available (neuromuscular blockade, prone position) adjuncts vs adjuncts requiring specialized equipment (extracorporeal membrane oxygenation, inhaled vasodilators, high-frequency ventilation) in patients in the first 48 h of moderate to severe ARDS (P/F ratio 150).Of 1,146 patients on invasive ventilation with moderate to severe ARDS, 811 patients (71%) received no adjunct within 48 h of ARDS onset. Of 335 (29%) that received adjunctive strategies, 252 (75%) received a single strategy, and 83 (25%) receiving more than one adjunct. Of ARDS nonsurvivors, 67% did not receive any adjunctive strategy in the first 48 h. Most patients (67%) receiving specialized adjuncts did not receive prone positioning or neuromuscular blockade. Patients that received adjuncts were more likely to have their ARDS recognized, be younger and sicker, have pneumonia, be more difficult to ventilate, and be in a European high-income country than those that did not receive adjuncts.Three in 10 patients with moderate to severe ARDS, and only one-third of nonsurvivors, received adjunctive strategies over the first 48 h of ARDS. A more consistent and evidence-driven approach to adjunct use may reduce costs and improve outcomes in patients with moderate to severe ARDS.ClinicalTrials.gov; No.: NCT02010073; URL: www.clinicaltrials.gov.

Rationale: No previous studies have examined the role of prehospital vulnerability in acute respiratory distress syndrome (ARDS) development and mortality in an acutely ill adult population. Objectives: To describe the association between prehospital vulnerability and 1) the development of ARDS, 2) 28-day mortality, and 3) 1-year mortality. Methods: This was a longitudinal prospective cohort study nested within the multicenter LIPS-A (Lung Injury Prevention Study-Aspirin) trial. We analyzed 301 participants who completed Vulnerable Elders Survey (VES) at baseline. Multivariable logistic regression and Cox regression analyses were used to describe the association between vulnerability and short-term outcomes (ARDS and 28-day mortality) and long-term outcomes (1-year mortality), respectively. Results: The VES score ranged from 0 to 10 (median [interquartile range], 2.0 [0–6]); 143 (47.5%) fit criteria for prehospital vulnerability (VES ≥ 3). Vulnerability was not significantly associated with ARDS development (10 [7.0%] vulnerable patients developed ARDS as per LIPS-A study criteria vs. 20 [12.7%] without vulnerability; P = 0.10; adjusted odds ratio [95% confidence interval (CI)], 0.54 [0.24–1.24]; P = 0.15). Nor was vulnerability associated with 28-day mortality (15 [10.5%] vulnerable patients were dead by Day 28 vs. 11 [7.0%] nonvulnerable patients; P = 0.28; adjusted odds ratio [95% CI], 0.95 [0.39–2.26]; P = 0.90). Vulnerability was significantly associated with 1-year mortality in hospital survivors (35 [26.9%] vs. 13 [9.3%]; adjusted hazard ratio [95% CI], 2.20 [1.10–4.37]; P = 0.02). Conclusions: In a population of adults recruited for their high risk of ARDS, prehospital vulnerability, measured by VES, was highly prevalent and strongly associated with 1-year mortality.

Supplemental Digital Content is available in the text., Objectives: To determine the association between prone positioning in nonintubated patients with coronavirus disease 2019 and frequency of invasive mechanical ventilation or inhospital mortality. Design: A nested case-matched control analysis. Setting: Three hospital sites in Bronx, NY. Patients: Adult coronavirus disease 2019 patients admitted between March 1, 2020, and April 1, 2020. We excluded patients with do-not-intubate orders. Cases were defined by invasive mechanical ventilation or inhospital mortality. Each case was matched with two controls based on age, gender, admission date, and hospital length of stay greater than index time of matched case via risk-set sampling. The presence of nonintubated proning was identified from provider documentation. Intervention: Nonintubated proning documented prior to invasive mechanical ventilation or inhospital mortality for cases or prior to corresponding index time for matched controls. Measurements and Main Results: We included 600 patients, 41 (6.8%) underwent nonintubated proning. Cases had lower Spo2/Fio2 ratios prior to invasive mechanical ventilation or inhospital mortality compared with controls (case median, 97 [interquartile range, 90–290] vs control median, 404 [interquartile range, 296–452]). Although most providers (58.5%) documented immediate improvement in oxygenation status after initiating nonintubated proning, there was no difference in worst Spo2/Fio2 ratios before and after nonintubated proning in both case and control (case median Spo2/Fio2 ratio difference, 3 [interquartile range, –3 to 8] vs control median Spo2/Fio2 ratio difference, 0 [interquartile range, –3 to 50]). In the univariate analysis, patients who underwent nonintubated proning were 2.57 times more likely to require invasive mechanical ventilation or experience inhospital mortality (hazard ratio, 2.57; 95% CI, 1.17–5.64; p = 0.02). Following adjustment for patient level differences, we found no association between nonintubated proning and invasive mechanical ventilation or inhospital mortality (adjusted hazard ratio, 0.92; 95% CI, 0.34–2.45; p = 0.86). Conclusions: There was no significant association with reduced risk of invasive mechanical ventilation or inhospital mortality after adjusting for baseline severity of illness and oxygenation status.

Introductions:Although randomized clinical trials showed no benefit from combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with standard chemotherapy for advanced non–small-cell lung cancer (NSCLC), better results might be obtained by combining EGFR-TKI with individual agents that are substrates for the adenosine triphosphate binding cassette transporters (ABCTs) because EGFR-TKIs can inhibit their efflux. The combination effects deserved to be further examined in vitro.Methods:The combination effects of gefitinib with three antimicrotubule agents (AMTAs), paclitaxel, docetaxel or vinorelbine, or with gemcitabine were tested in 17 NSCLC cell lines using the tetrazolium colorimetric assay and classical isobole method. The effects of drug combinations, identified by the values of mean combination index (mCIs), were correlated with the expression levels of ABCTs. Dose-versus-log-response curves were analyzed to further evaluate the possible mechanisms of drug interactions.Results:Synergistic gefitinib/AMTA interactions were observed in the tested cell lines. The synergism was more robust in the four lines overexpressing de novo or acquired P-glycoprotein (Pgp; individual mCIs range, 0.484–0.859; all p values were < 0.05), or in 12 cell lines exhibiting no sensitizing EGFR mutations (group mCIs for gefitinib/paclitaxel, gefitinib/docetaxel, and gefitinib/vinorelbine were 0.869, 0.82, and 0.853, respectively. All p values were < 0.02). The synergism could be observed in cells expressing nearly undetectable Pgp and other ABCTs tested in this study. The combination of gefitinib/gemcitabine was additive (mCI = 1.027).Conclusions:Combined gefitinib/AMTAs showed synergism in NSCLC cells harboring no sensitizing EGFR mutations. Gefitinib could enhance AMTA effects through mechanisms not restricted to Pgp blockage.

Introduction: Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined. Methods: Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log-response curves (DRCs) were analyzed to evaluate possible resistance mechanisms. Results: Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index=1.184, 95% confidence interval=1.12–1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 μM can interfere with cisplatin cell entry (at concentrations >1–3 μM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines. Conclusions: In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials.

BackgroundSevere malaria may be complicated by the acute respiratory distress syndrome (ARDS), which is associated with a high mortality. In the present report, a series of three cases of imported malaria complicated by refractory severe ARDS supported with extracorporeal membrane oxygenation (ECMO) is presented.MethodsOne female and two male adult patients (ages 39 to 53) were included. Two patients hadPlasmodium falciparuminfection and one patient hadPlasmodium vivaxandPlasmodium ovaleco-infection. Anti-malarial therapy consisted in intravenous quinine (in two patients) and intravenous quinidine (in one patient), plus clindamycin or doxycycline.ResultsDespite lung protective ventilation, a conservative strategy of fluid management, corticosteroids (two patients), prone position (two patients) and inhaled nitric oxide (one patient), refractory severe ARDS supervened (PaO2to FiO2ratio 68) and venovenous ECMO was then initiated. In one patient, a bicaval dual-lumen cannula was inserted; in the two other patients, a two-site configuration was used. Two patients survived to hospital-discharge (duration of ECMO support: 8.5 days) and one patient died from nosocomial sepsis and multi-organ failure after 40 days of ECMO support.ConclusionsECMO support allowed adequate oxygenation and correction of hypercapnia under lung protective ventilation, therefore reducing ventilator-induced lung injury. ECMO referral should be considered early in malaria complicated by severe ARDS refractory to conventional treatment.

Background Combined epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with chemotherapy is believed to be more effective in treating non-small-cell lung cancer (NSCLC) with sensitizing-EGFR mutation (SEM). This hypothesis failed to be realized clinically and needs to be examined in vitro. Materials and methods Using the tetrazolium colorimetric assay and classical isobole method, we investigated the combination effects of 6 gefitinib-chemotherapeutic doublets (gefitinib/cisplatin, gemcitabine, pemetrexed, paclitaxel, docetaxel, or vinorelbine) in a panel of 15 NSCLC cell lines. Results Upon treatment with the 6 gefitinib-chemotherapeutic doublets, the 12 cell lines that did not harbor SEM displayed a broad spectrum of group results, from obvious synergism to robust antagonism. The values of group mean combination index (mCIs) ranged from 0.769 to 1.201. In contrast, the 3 cell lines with SEM showed a tendency toward consistent antagonism to the tested doublets, impressively, with a narrow range of higher group mCIs (0.993–1.141). In the presence of gefitinib, the SEM or gefitinib-sensitive group was more chemo-refractory than the non-SEM (index of chemo-refractoriness (RI): 69.33 versus 42.67; P =0.036) or gefitinib-resistant group (68.25 versus 40.64, P =0.0108), respectively. The results of using the gefitinib/drug combinations with the gefitinib-sensitive non-SEM cell line H322 and the gefitinib-resistant EGFR mutant H820 shared patterns similar to those with the SEM and non-SEM cell lines, respectively. Conclusion Gefitinib-treated EGFR-TKI-sensitive NSCLC cells showed a wide spectrum of chemo-refractoriness, suggesting that concomitantly combined EGFR-TKI-chemotherapy might not be a good treatment strategy for NSCLC harboring SEM.